And it's whispered that soon If we all call the tune Then the piper will lead us to reason —Led Zeppelin, “Stairway to Heaven”

Framed by the rediscovery of Mendel's studies in 1900 and the determination of the sequence of the human genome in 2000, the 20th century, it can be argued, was “the century of the gene.” Over its span, genetics rose from obscurity to form a cornerstone of evolutionary biology's Modern Synthesis, and the physical and chemical bases of inheritance and mutation were explained, the genetic code deciphered, the riddle of antibody diversity solved, a several hundred billion dollar industry born, and new tools invented that have revolutionized fields from forensic science to paleoanthropology.

Now seems a fitting time to look back upon this parade of great achievements and to ponder what the future may bring. In her new book, noted science historian Evelyn Fox Keller ventures in both directions; she covers a few highlights in the history of genetics and offers a bit of crystal ball-gazing. But The Century of the Gene is less a celebration of the triumphs of genetics than an appeal to biologists to shed their gene-centric mindset so as to usher in a new “Cambrian Period” of biological reason.

Keller explains that one major impetus for the book was “the call for functional genomics,” a recent buzzword for the functional analysis of genes defined by genomic sequencing instead of classical genetics. In this new era, Keller sees “at least tacit acknowledgment of how large a gap between genetic ‘information' and biological meaning really is” and “an acknowledgement of the limitations of the most extreme forms of reductionism that had earlier held sway.” In a fairly short, very readable text, Keller develops the theme that both current genetic parlance and the reductionist approach are inadequate for explaining our expanding biological knowledge. She finds that they threaten to limit the future intellectual growth and public understanding of the discipline. And she suggests that new concepts, terms, and ways of thinking will be necessary to loosen the grip that genes have held on the imaginations of life scientists.

Keller perceives “ever-widening gaps between our starting assumptions and the actual data that the new molecular tools are now making available.” For starters, she tackles no less than “the gene” as an outmoded term and concept. She alleges that the “prowess of new analytic techniques and the sheer weight of the findings they have enabled have brought the concept of the gene to the verge of collapse.” Yet we are never really told which techniques and what mass of findings have precipitated this supposed crisis. To be sure, the analysis of eukaryotic genes has revealed that more structural features (introns, dispersed cis-regulatory elements, alternative splice sites) are involved in the regulation of the transcription and processing of RNA transcripts than for typical bacterial genes. And, in multicellular organisms, genes do encode products that function in more than one place and at more than one time (although pleiotropy, a perfectly well-understood term and concept, is not mentioned). But structural complexity or multifunctionality do not disable the term “gene” anymore than the range of architectural complexity or variety of uses of “buildings,” from shacks to palaces, renders that noun obsolete.

“Genetic program” is another term that draws Keller's fire. She traces its origin to the pioneering work of Jacques Monod and François Jacob in the early 1960s, which extrapolated from the principles of enzyme induction in bacteria to metazoan development. Keller objects to the notion that there is a program contained within the genome. She rejects model descriptions such as a “genetic switching network” on the grounds that this phrase “harbors a potentially treacherous ambiguity” that fails to distinguish between genes as the source of the program and as entities upon which the program acts.

Granted there is some sloppiness in the uses and connotations of terminology, but does this really threaten scientific communication or progress? Although there is no consensus definition of “program” or “networks,” these terms are most often encountered and understood in the context of the regulatory interactions that link groups of genes and gene products in developmental processes. Many of these linkages have recently been elucidated in considerable detail for key events in a variety of species. Keller could have presented these new findings to illustrate concrete points about the formal logic and mechanisms underpinning the architecture of genetic regulatory systems. But she is less concerned with explaining empirical insights than with critiquing potential semantic ambiguities. The reader is left to weigh her argument without the benefit of understanding the substance of new discoveries.

This lack of scientific substance and a narrowness of explanations weakens Keller's overall case. In another example, Keller argues that the inadequacies of genetic methods and logic are laid bare by the existence of genetic redundancy. Quoting from sources now 7 to 10 years old, she makes much out of the frustrations of gene knockout studies in the mouse that yielded slight or no observable phenotypes. She suggests that genetic redundancy exposes a critical, insurmountable limit on genetic analysis. But in presenting only these earlier challenges and no subsequent solutions, the resulting message (that reductionism has hit a wall) is misleading. Keller offers a limited (and untestable) explanation for redundancy in computer and engineering terms, which indicates that redundancy is what we should expect evolution to produce. But the extent of redundancy is contingent upon the history of the particular group. Those lineages that have experienced genome-wide duplications (as occurred at the base of the vertebrates and again in some teleost fish) or polyploidy display greater redundancy and pose more obstacles to genetic analysis. Nevertheless, molecular biologists and geneticists have devised many ingenious ways to identify potentially redundant genes and to elucidate the biological roles of the products they encode. The lack of recognition of such efforts and the glaring omission of any mention of the expanding success of the genetic analyses of complex traits (in development, evolution, and medicine) leave an unbalanced picture of the intellectual and technical forces that now shape genetic and molecular approaches to challenging biological questions.

The call for functional genomics to which Keller has reacted is not an acknowledgment of the limitations of reductionism. On the contrary, it is a call for tools and technologies to practice reductionism systematically on a much larger, genome-wide scale. The dangers and demise of reductionist biology have been pronounced before, only to be mocked by waves of innovation and discovery. This piper's tune is likely to go unheeded.